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Senataxin Plays an Essential Role with DNA Damage Response Proteins in Meiotic Recombination and Gene Silencing


Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2), plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops), and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx−/− revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome.


Vyšlo v časopise: Senataxin Plays an Essential Role with DNA Damage Response Proteins in Meiotic Recombination and Gene Silencing. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003435
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003435

Souhrn

Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2), plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops), and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx−/− revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome.


Zdroje

1. MoreiraMC, KlurS, WatanabeM, NemethAH, Le BerI, et al. (2004) Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 36: 225–227.

2. AnheimM, MongaB, FleuryM, CharlesP, BarbotC, et al. (2009) Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain 132 (Pt 10) 2688–2698.

3. ChenYZ, BennettCL, HuynhHM, BlairIP, PulsI, et al. (2004) DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 74: 1128–1135.

4. UrsicD, ChinchillaK, FinkelJS, CulbertsonMR (2004) Multiple protein/protein and protein/RNA interactions suggest roles for yeast DNA/RNA helicase Sen1p in transcription, transcription-coupled DNA repair and RNA processing. Nucleic Acids Res 32: 2441–2452.

5. SuraweeraA, BecherelOJ, ChenP, RundleN, WoodsR, et al. (2007) Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage. J Cell Biol 177: 969–979.

6. SuraweeraA, LimY, WoodsR, BirrellGW, NasimT, et al. (2009) Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation. Hum Mol Genet 18: 3384–3396.

7. Skourti-StathakiK, ProudfootNJ, GromakN (2011) Human Senataxin Resolves RNA/DNA Hybrids Formed at Transcriptional Pause Sites to Promote Xrn2-Dependent Termination. Mol Cell 42: 794–805.

8. HuertasP, AguileraA (2003) Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell 12: 711–721.

9. LiX, ManleyJL (2005) Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122: 365–378.

10. MischoHE, Gomez-GonzalezB, GrzechnikP, RondonAG, WeiW, et al. (2011) Yeast Sen1 helicase protects the genome from transcription-associated instability. Mol Cell 41: 21–32.

11. Yüce-PetronczkiO, WestSC (2012) Senataxin, defective in the neurogenerative disorder AOA-2, lies at the interface of transcription and the DNA damage response. Mol Cell Biol doi:10.1128/MCB.01195-12.

12. AlzuA, BermejoR, BegnisM, LuccaC, PicciniD, et al. (2012) Senataxin Associates with Replication Forks to Protect Fork Integrity across RNA-Polymerase-II-Transcribed Genes. Cell 151: 835–46.

13. GuyenetSJ, FurrerSA, DamianVM, BaughanTD, La SpadaAR, et al. (2010) A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp 21 doi:pii: 1787. 10.3791/1787.

14. BarlowC, HirotsuneS, PaylorR, LiyanageM, EckhausM, et al. (1996) Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86: 159–171.

15. XuY, AshleyT, BrainerdEE, BronsonRT, MeynMS, et al. (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10: 2411–2422.

16. CohenPE, PollardJW (2001) Regulation of meiotic recombination and prophase I progression in mammals. Bioessays 23: 996–1009.

17. YazawaT, YamamotoT, NakayamaT, HamadaS, AbeS (2000) Conversion from mitosis to meiosis: morphology and expression of proliferating cell nuclear antigen (PCNA) and Dmc1 during newt spermatogenesis. Dev Growth Differ 42: 603–611.

18. ZhaoM, ShirleyCR, MounseyS, MeistrichMI (2004) Nucleoprotein transitions during spermiogenesis in mice with transition nuclear protein Tnp1 and Tnp2 mutations. Biol Reprod 71: 1016–1025.

19. KeeneyS (2001) Mechanism and control of meiotic recombination initiation. Curr Top Dev Biol 52: 1–53.

20. RogakouE, BoonP, RedonC, BonnerWM (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146: 905–916.

21. HunterN, BornerGV, LichtenM, KlecknerR (2001) Gamma-H2AX illuminates meiosis. Nat Genet 27: 236–238.

22. Turner JM, AprelikovaO, XuX, WangR, KimS, et al. (2004) BRCA1, histone H2AX phosphorylation, and male meiotic sex chromosome inactivation. Curr Biol 14: 2135–2142.

23. TurnerJM, MahadevaiahSK, ElliottDJ, GarchonHJ, PehrsonJR, et al. (2002) Meiotic sex chromosome inactivation in male mice with targeted disruptions of Xist. J Cell Sci 115 (Pt 21) 4097–4105.

24. TurnerJM, MahadevaiahSK, Fernandez-CapetilloO, NussenzweigA, XuX, et al. (2005) Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet 37: 41–47.

25. AshleyT, PlugAW, XuJ, SolariAJ, ReddyG, et al. (1995) Dynamic changes in Rad51 distribution on chromatin during meiosis in male and female vertebrates. Chromosoma 104: 19–28.

26. BakerSM, PlugAW, ProllaTA, BronnerCE, HarrisAC, et al. (1996) Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat Genet 13: 336–342.

27. HunterN, BortsRH (1997) Mlh1 is unique among mismatch repair proteins in its ability to promote crossing-over during meiosis. Genes Dev 11: 1573–1582.

28. AndersonLK, ReevesA, WebbLM, AshleyT (1999) Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein. Genetics 151: 1569–79.

29. BoguslawskiSJ, SmithDE, MichalakMA, MickelsonKE, YehleCO, et al. (1986) Characterization of monoclonal antibody to DNA:RNA and its application to immunodetection of hybrids. J Immunol Methods 89: 123–130.

30. HuZ, ZhangA, StorzG, GottesmanS, LepplaSH (2006) An antibody-based microarray assay for small RNA detection. Nucleic Acids Res 34: e52.

31. PageJ, de la FuenteR, ManterolaM, ParraMT, VieraMT, et al. (2012) Inactivation or non-reactivation: what accounts better for the silence of sex chromosomes during mammalian male meiosis? Chromosoma 121: 307–326.

32. Fernandez-CapetilloO, MahadevaiahSK, CelesteA, RomanienkoPJ, Camerini-OteroRT, et al. (2003) H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell 4: 497–508.

33. IchijimaY, IchijimaM, LouZ, NussenzweigA, Camerini-OteroRD, et al. (2011) MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells. Genes Dev 25: 959–971.

34. HandelMA (2004) The XY body: a specialized meiotic chromatin domain. Exp Cell Res 296: 57–63.

35. WangPJ, PageDC, McCarreyJR (2005) Differential expression of sex-linked and autosomal germ-cell-specific genes during spermatogenesis in the mouse. Hum Mol Genet 14: 2911–2918.

36. RoyoH, PolikiewiczG, MahadevaiahSK, ProsserH, MitchellM, et al. (2010) Evidence that meiotic sex chromosome inactivation is essential for male fertility. Curr Biol 20: 2117–2123.

37. BaarendsWM, WassenaarE, van der LaanR, HoogerbruggeJ, Sleddens-LinkelsE, et al. (2005) Silencing of unpaired chromatin and histone H2A ubiquitination in mammalain meiosis. Mol Cell Biol 25: 1041–1053.

38. RomanienkoPJ, Camerini-OteroRD (2000) The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell 6: 975–987.

39. PittmanDL, CobbJ, SchimentiKJ, WilsonLA, CooperDM, et al. (1998) Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol Cell 1: 697–705.

40. CressmanVL, BacklundDC, AvrutskayaAV, LeadonSA, GodfreyV, et al. (1999) Growth retardation, DNA repair defects, and lack of spermatogenesis in BRCA1-deficient mice. Mol Cell Biol 19: 7061–7075.

41. EdelmannW, CohenPE, KneitzB, WinandN, LiaM, et al. (1999) Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet 21: 123–127.

42. KneitzB, CohenPE, AvdievichE, ZhuL, KaneMF, et al. (2000) MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev 14: 1085–1097.

43. KolasNK, SvetlanovA, LenziML, MacalusoFP, LipkinSM, et al. (2005) Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I. J Cell Biol 171: 447–458.

44. XuX, AprelikovaOI, MoensP, DengCX, FurthPA (2003) Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice. Development 130: 2001–2012.

45. AguileraA (2005) mRNA processing and genomic instability. Nat Struct Mol Biol 12: 737–738.

46. Castellano-PozoM, Garcia-MuseT, AguileraA (2012) R-loops cause replication impairment and genome instability during meiosis. EMBO Reports 13: 923–929.

47. GanW, GuanZ, LiuJ, GuiT, ShenK, et al. (2011) R-loop meidated genomic instability is caused by impairement of replication fork progression. Genes Dev 25: 2041–2056.

48. SordetO, NakamuraAJ, RedonCE, PommierY (2010) DNA double-strand breaks and ATM activation by transcription-blocking DNA lesions. Cell Cycle 9: 274–278.

49. TurnerJM (2007) Meiotic sex chromosome inactivation. Development 134: 1823–1831.

50. McKeeBD, HandelMA (1993) Sex chromosomes, recombination, and chromatin conformation. Chromosoma 102: 71–80.

51. MahadevaiahSK, TurnerJM, BaudatF, RogakouEP, de BoerP, et al. (2001) Recombinational DNA double-strand breaks in mice precede synapsis. Nat Genet 27: 271–276.

52. BurgoynePS, MahadevaiahT, TurnerSK (2009) The consequences of asynapsis for mammalian meiosis. Nat Rev Genet 10: 207–216.

53. ZhuQ, PaoGM, HuynhAM, SuhH, TonnuN, et al. (2011) BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 7363: 179–184.

54. ChanW, CostantinoN, LiR, LeeSC, SuQ, et al. (2007) A recombineering based approach for high-throughput conditional knockout targeting vector construction. Nucleic Acids Res 35: e64.

55. ChouAH (2008) Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis 31: 89–101.

56. ThomasPSJr (2006) Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy. Hum Mol Genet 15: 2225–2238.

57. DitzlerS, StoeckJ, LeBlancM, KooperbergC, HansenS, et al. (2003) A Rapid Neurobehavioral Assessment Reveals that FK506 Delays Symptom Onset in R6/2 Huntington's Disease Mice. Preclinica Research Articles 1: 115–126.

58. EddyEM (2002) Male Germ cell gene expression. Recent Prog Horm Res 57: 103–28.

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